Myocardial infarction (MI) resulting in the loss of fully functional myocardium is the major cause (50-70%) of heart failure (HF), which continues to be a major health problem in the U.S. Unfavourable post-MI healing and extended MI size lead to detrimental cardiac remodeling that prone the damage heart to transition to HF. At this stage, there are no clinical therapies available to halt this downhill course with the aim to promote myocardial regeneration and limit MI size. This proposal, accordingly, has direct health relevance as it will characterize and test a novel therapeutic principle and target, respectively, to favourably modulate post-MI inflammation and regeneration with the ultimate goal of translating our findings clinically. In our previous work, we have extensively characterized the intracellular role of S100A1 in cardiomyocytes as a critical regulator of calcium (Ca2+) cycling exerting a non-detrimental positive inotropic effect in normal hearts and protect and rescue injured hearts from post-MI HF. Here, we propose a novel extracellular role for S100A1 when released by ischemic myocardium to act as a local and systemic signal of cardiac damage both favourably modulating cardiac healing and promoting cardiac tissue regeneration through a unique interaction with the bone marrow (BM). Taking advantage of genetically manipulated mouse models with different cardiac S100A1 expression levels and complementary biochemical strategies to specifically neutralize and supplement MI-released extracellular S100A1, we will determine the impact of damage-released S100A1 on post-MI healing and regeneration and test the therapeutic effect of exogenous S100A1. The Central Hypothesis of this proposal is that cardiomyocyte-released S100A1 protein acts as an endogenous signaling molecule that triggers a favourable inflammatory response in the infarcted heart and improves cardiac regeneration post-MI through recruitment of BM stem cells. The specific aims are: Aim 1: To determine the local role of cardiomyocyte- released S100A1 to modulate the inflammatory response of the infarcted heart in vivo and the underlying molecular mechanisms and signaling pathways in cardiac S100A1 target cells ex vivo. Aim 2: To determine the systemic role of cardiomyocyte-released S100A1 to modulate bone marrow contribution to the regeneration of the infarcted heart in vivo and characterize the underlying molecular mechanisms and signaling cascades in extra-cardiac S100A1 target cells ex vivo. Aim 3: To examine the therapeutic role of exogenous S100A1 as a target to modulate cardiac healing, regeneration and subsequent remodeling after myocardial infarction in vivo. PUBLIC HEALTH RELEVANCE stems from our major aim to characterize and test a novel therapeutic cardiac target to improve healing and regeneration after myocardial infaction, which is the major reason for heart failure (HF) in the U.S. At this stage, there is no clinical therapy available to promote cardiac regeneration to prevent HF.